Hepatocellular carcinoma (HCC) is one of the most prevalent human malignancies worldwide, with an increasing incidence in the United States (Parkin et al., CA Cancer J. Clin. 55(2):74-108, 2005). HCC arises most frequently in patients with inflammatory livers resulting either from viral hepatitis caused by infection with hepatitis B virus (HBV) or hepatitis C virus (HCV), or from metabolic disorders or toxic insults. Viral hepatitis contributes to over 80% of HCC cases in the world (Thorgeirsson and Grisham, Nat. Genet. 31(4):339-3465, 2002; Budhu and Wang, J. Leukoc. Biol. 80(6):1197-1213, 2006). One of the key features of HCC is its gender disparity with a striking male dominance (i.e. 2-6 times more common in males than in females) (El Serag and Rudolph, Gastroenterology 132(7):2557-2576, 2007). Classical in vivo carcinogenesis experiments also reveal a higher susceptibility to HCC in male rodents (Ghebranious and Sell, Hepatology 27(2):383-391, 1998; Nakatani et al., Jpn. J. Cancer Res. 92(3):249-256, 2001; Rogers et al., Cancer Res. 67(24):11536-11546, 2007; Naugler et al., Science 317(5834):121-124, 2007). Moreover, female HCC patients tend to have a longer survival than male patients (Ng et al., Cancer 75(1):18-22, 1995; Dohmen et al., J. Gastroenterol. Hepatol. 18(3):267-272, 2003; Tangkijvanich et al., World J. Gastroenterol. 10(11):1547-1550, 2004.). These results indicate that tumor biology and host microenvironment may differ significantly between males and females.
A recent study suggests that the gender disparity observed in HCC may be due to an induction of Kupffer cell-produced interleukin-6 (IL-6), which can be inhibited by estrogen (Naugler et al., Science 317(5834):121-124, 2007). Consistent with this idea, other studies have revealed that serum IL-6 is highly elevated in several aggressive malignancies including HCC, and its expression, which can be produced by tumor cells, is associated with metastatic diseases and poor prognosis (Ashizawa et al., Gastric Cancer 8(2):124-131, 2005; Porta et al., Ann. Oncol. 19(2):353-358, 2008). These studies suggest that the procarcinogeneic activities of IL-6 may be regulated by sex hormones and tumors with activated IL-6 may be biologically distinct and more aggressive.
Surgery remains the only effective treatment modality for HCC to date with a potential to cure. However, only about 10-20% patients with HCC are currently eligible for surgical intervention. In addition, patients who receive curative resections often have a high frequency of relapse. Thus, a need remains to develop diagnostic tools that provide a sufficient resolution in assisting patient stratification for prognosis and therapy.